Uric acid is present as the final metabolite of purine base-containing substances in humans. A serum uric acid level of more than 7 mg/dL is defined as hyperuricemia, of which the causative factors include reduction in uric acid excretion, overproduction of purine base-containing substances and increase in the metabolism of purine base-containing substances. The population with hyperuricemia is on an upward trend as of 2010 (Non Patent Literature 1).
When hyperuricemia becomes chronic, the risk of developing gouty arthritis, urolithiasis, gouty nephropathy and other pathological conditions increases. Recent epidemiological studies indicate that hyperuricemia is an independent risk factor for cardiovascular and cerebrovascular diseases. In addition, hyperuricemia is a precipitating factor for diabetes mellitus and hyperlipidemia, and is considered important as a clinically useful indicator (biomarker) of various lifestyle-related diseases (Non Patent Literature 2).
Thus, hyperuricemia has an aspect of lifestyle-related disease, and the incidence of hyperuricemia and the younger onset of hyperuricemia have recently increased as well as the incidence of mild and borderline hyperuricemia, to which medication treatment is usually not applied. Accordingly, not only hyperuricemia therapeutic agents, but also relevant health foods such as dietary supplements have been developed (Patent Literature 1 and 2). The development of products other than therapeutic agents is expected to be expanded in the near future.
However, animal models for studies on hyperuricemia are difficult to produce. This is because non-primate mammals have an abundance of uricase (uricolytic enzyme) in hepatocytes, which enzyme degrades uric acid into allantoin (Non Patent Literature 3). In addition, transgenic uricase-deficient model animals result in death (Non Patent Literature 3), which is the reason why uricase deficiency in non-primate mammals cannot produce hyperuricemia.
Currently, an animal model of hyperuricemia induced by the uricase inhibitor oxonic acid (Non Patent Literature 4) is used for studies on hyperuricemia. However, this model has the disadvantage of the need for continuous administration of oxonic acid for retention of pathological conditions. Therefore, in the evaluation for hyperuricemia therapeutic agents, this animal model cannot be used without concern about the interaction of oxonic acid with a candidate therapeutic agent to be evaluated. In addition, considering that this model can produce uricase, it is dubious whether the pathological conditions of hyperuricemia in this model are equivalent to those in humans, which are naturally deficient in uricase (Non Patent Literature 5 and 6).
In addition to the oxonic acid-induced hyperuricemia model, high-purine diet-induced hyperuricemia rodent models are known. These models can be produced by dietary administration or oral gavage administration of purines such as inosinic acid, hypoxanthine and RNA. However, since these dietary hyperuricemia mammal models have uricase, the plasma uric acid concentrations are often not sufficiently high. For this reason, these models are usually used with oxonic acid administration, which is disadvantageous as with the case of the oxonic acid-induced animal model.
Non Patent Literature 7 and 8 teach that chimeric mice produced by transplantation of human hepatocytes to immunodeficient mice with liver dysfunction may develop hyperuricemia and can be a hyperuricemia model producible without purine base-rich substance administration or chemical administration.
However, the development of hyperuricemia is observed in only some of the chimeric mice according to NOB Patent Literature 7 and 8. In addition, these chimeric mice have low weights and thus difficult to use as an experimental animal.